Endocannabinoid transporters

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Most neurotransmitters are water-soluble and require transmembrane proteins to transport them across the cell membrane. The endocannabinoids (anandamide, AEA, and 2-arachidonoylglycerol, 2-AG) on the other hand, are non-charged lipids that readily cross lipid membranes.[1][2][3][4][5] However, since the endocannabinoids are water immiscible, protein transporters have been described that act as carriers to solubilize and transport the endocannabinoids through the aqueous cytoplasm. These include the heat shock proteins (Hsp70s) and fatty acid binding proteins for anandamide (FABPs).[6][7] FABP inhibitors attenuate the breakdown of anandamide by the enzyme fatty acid amide hydrolase (FAAH) in cell culture.[6] One of these inhibitors (SB-FI-26), isolated from a virtual library of a million compounds, belongs to a class of compounds (named the "truxilloids') that act as a anti-nociceptive agent with mild anti-inflammatory activity in mice.[8] These truxillic acids and their derivatives have been known to have anti-inflammatory and anti-nociceptive effects in mice[9] and are active component of a Chinese herbal medicine ((-)-Incarvillateine Incarvillea sinensis) used to treat rheumatism and pain in human. The blockade of anandamide transport may, at least in part, be the mechanism through which these compounds exert their anti-nociceptive effects.

References[edit]

  1. ^ Kaczocha, Martin; Lin, Qingqing; Nelson, Lindsay D.; McKinney, Michelle K.; Cravatt, Benjamin F.; London, Erwin; Deutsch, Deutsch (2012). "Anandamide Externally Added to Lipid Vesicles Containing-Trapped Fatty Acid Amide Hydrolase (FAAH) Is Readily Hydrolyzed in a Sterol-Modulated Fashion". ACS Chemical Neuroscience 3 (5): 364–368. doi:10.1021/cn300001w. PMID 22860204. 
  2. ^ Bojesen, Inge N.; Hansen, Harald S. (2005). "Membrane transport of anandamide through resealed human red blood cell membranes". The Journal of Lipid Research. 46 no. (8): 1652–1659. doi:10.1194/jlr.M400498-JLR200. 
  3. ^ Kaczocha, Martin; Hermann, Anita; Glaser, Sherrye T.; Bojesen, Inge N.; Deutsch, Dale G. (2006). "Anandamide Uptake Is Consistent with Rate-limited Diffusion and Is Regulated by the Degree of Its Hydrolysis by Fatty Acid Amide Hydrolase". The Journal of Biological Chemistry 281 (14): 9066–9075. doi:10.1074/jbc.M509721200. PMID 16461355. 
  4. ^ Sandberg, A.; Fowler, C.J. (2005). "Measurement of saturable and non-saturable components of anandamide uptake into P19 embryonic carcinoma cells in the presence of fatty acid-free bovine serum albumin.". Chemistry and Physics of Lipids 134 (2): 131–139. doi:10.1016/j.chemphyslip.2004.12.010. PMID 15784231. 
  5. ^ Di Pasquale, E.; Chahinian, H.; Sanchez, P.; Fantini, J. (2009). "The Insertion and Transport of Anandamide in Synthetic Lipid Membranes Are Both Cholesterol-Dependent" [Translated title]. PLoS ONE 4 (3): e4989. doi:10.1371/journal.pone.0004989. PMID 19330032. 
  6. ^ a b Kaczocha, M.; Glaser, S.T.; Deutsch, D.G. (2009). "Identification of intracellular carriers for the endocannabinoid anandamide". Proceedings of the National Academy of Sciences of the United States of America 106 (15): 6375–6380. doi:10.1073/pnas.0901515106. PMC 2669397. PMID 19307565. 
  7. ^ Oddi, S.; Fezza, F.; Pasquariello, N.; D'Agostino, A.; Catanzaro, G.; De Simone, C.; Rapino, C.; Finazzi-Agro, A.; Maccarrone, M. (2009). "Molecular identification of albumin and Hsp70 as cytosolic anandamide-binding proteins". Chemistry & Biology 16 (6): 624–632. doi:10.1016/j.chembiol.2009.05.004. PMID 19481477. 
  8. ^ Berger, W.T.; Ralph, B.P.; Kaczocha, M.; Sun, J.; Balius, T.E.; Rizzo, R.C.; Haj-Dahmane, S.; Ojima, I.; Deutsch, D.G. (2012). "Targeting Fatty Acid Binding Protein (FABP) Anandamide Transporters – A Novel Strategy for Development of Anti-Inflammatory and Anti-Nociceptive Drugs". PLoS ONE 12 (7): e50968. doi:10.1371/journal.pone.0050968. 
  9. ^ Nakamura, M.; Chi, Y.M.; Yan, W.M.; Nakasugi, Y.; Yoshizawa, T.; Irino, N.; Hashimoto, F.; Kinjo, J.; Nahara, T.; Sakurada, S. (1999). "Strong antinociceptive effect of incarvillateine, a novel monoterpene alkaloid from Incarvillea sinensis". Journal of Natural Products 62 (9): 1293–1294. doi:10.1021/np990041c. PMID 10514316.